Introduction: Increased density and sensitivity of lymphocyte Type II glucocorticoid receptors has been reported in subjects with post-traumatic stress disorder (PTSD). However, central glucocorticoid receptor sensitivity has not been previously assessed in PTSD. A surrogate marker of central glucocorticoid receptor sensitivity that has been applied in studies of Alzheimer's disease has been to use PET measures of hydrocortisone-mediated inhibition of cerebral glucose metabolism. We assessed central glucocorticoid receptors in PTSD by evaluating changes in glucose metabolism using 18 FDG -PET following the administration of hydrocortisone. Differences in neuropsychological test performance and response to a traumatic script under hydrocortisone and placebo conditions were also evaluated. Methods: 10 subjects (9 women, 1 man) with PTSD according to the DSM IV and 9 healthy subjects (8 women, 1 man) received double-blind, intravenous injections of placebo or 30 milligrams of hydrocortisone one week apart. Using a GE Advance PET camera, a static emission scan of cerebral glucose uptake was initiated 45 min after injection of 5 mCi of 18 FDG. The FDG was injected 90 minutes after hydrocortisone/placebo administration. Hydrocortisone effects on regional metabolism were assessed by comparing the placebo and hydrocortisone images using MRI-based ROI analysis to assess structures where glucocorticoid effects were hypothesized a priori. In addition, a post-hoc, voxel-by-voxel analysis was performed using SPM99 to assess glucocorticoid effects in other structures. Hippocampal and non-hippocampal mediated neuropsychological tests were administered, and neuroendocrine and autonomic response to a taped script of the primary trauma was evaluated Results: The mean age of the patients was 39 + 10 years and healthy subjects was 35 + 10 years. The mean Clinician Administered PTSD Scale (CAPS) score for the patients was 86 + 17. Following hydrocortisone administration glucose metabolism significantly increased in the left amygdala, left and medial cerebellum in healthy subjects [p(uncorrected) = 0.001]. The increase in glucose metabolism in the amygdala and cerebellum in healthy subjects following hydrocortisone administration was significantly greater than the change seen in patients with PTSD. Patients with PTSD had an increase in glucose metabolism in the left posterior orbital cortex and left inferior temporal cortex [p(uncorrected) = 0.001], but these responses did not significantly differ between the PTSD and control groups. Differences in neuropsychological test performance and response to trauma reminders are currently being analyzed. Conclusions: These preliminary findings suggest a differential response to hydrocortisone in several brain regions, particularly the amygdala, in PTSD patients compared to healthy subjects. Further conclusions regarding changes in glucose metabolism relative to PTSD symptoms, and effects of hydrocortisone on neuropsychological test performance and trauma scripts will be determined as the sample collection in this ongoing study is completed.